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Abstract
Background Sex differences in atrial fibrillation (AF) are observed in terms of comorbidities, symptoms, therapies received, AF progression and cardiovascular complications.
Methods We assessed the differences in prevalence and the determinants of AF progression, as well as the clinical characteristics and quality of life (QoL), between women and men with paroxysmal AF included in the RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) study. At baseline, extensive phenotyping was done. To assess AF progression, implantable loop recorder (ILR) monitoring was used throughout follow-up. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of paroxysmal AF (>3% burden increase).
Results 417 patients were included, 179 (43%) of whom were women. Women were older (median 67 years vs 63 years, p<0.001), less often had coronary artery disease (n=11 (6%) vs n=36 (16%), p=0.003), had more obesity (n=57 (32%) vs n=50 (21%), p=0.013), had less epicardial and pericardial fat (median 144 (interquartile range [IQR] 94–191) mL vs 199 (IQR 146–248) mL, p<0.001; and median 89 (ICQ 61–121) mL vs 105 (IQR 83–133) mL, p<0.001, respectively) and had more impaired left atrial function. The median follow-up was 2.2 (1.6–2.8) years. 51 of 417 patients (5.5% per year) showed AF progression (15/179 (8.4%) women and 36/238 (15.1%) men, p=0.032). Multivariable analysis showed tissue factor pathway inhibitor, N-terminal prohormone brain natriuretic peptide (NT-proBNP) and PR interval being associated with AF progression in women and factor XIIa:C1 esterase, NT-proBNP and proprotein convertase subtilisin/kexin type 9 in men. QoL was not different between sexes.
Conclusion Despite older age, the incidence of AF progression was lower in women. Parameters associated with AF progression varied in part between sexes, suggesting different underlying pathophysiological mechanisms.
- Atrial Fibrillation
- Biomarkers
- Arrhythmias, Cardiac
Data availability statement
Data are available upon reasonable request. The data underlying this article are available on request from the principal investigator.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Progression of atrial fibrillation (AF) has been associated with an increased risk of cardiovascular morbidity and mortality and reduced efficacy of pharmacological and interventional rhythm control strategies.
The clinical profile of women and men with paroxysmal AF is different and may lead to differences in AF progression.
WHAT THIS STUDY ADDS
This RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) post-hoc analysis showed that the clinical profile is indeed different between women and men.
Furthermore, the incidence of AF progression was lower in women compared with men.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The results of this study showed that parameters associated with AF progression varied in part between sexes, suggesting different underlying pathophysiological mechanisms which could aid clinicians in a holistic approach to optimal treatment for AF.
Introduction
Evidence is growing on sex-specific differences in incidence, prevalence, risk factors and comorbidities, and outcomes of patients with atrial fibrillation (AF).1–4 Women are generally older and have a different comorbidity profile.1 2 5 Registry studies have reported a higher incidence of AF-related stroke and systemic thromboembolism in women than in men with AF,6–8 and potentially a higher mortality.7 9 10 Further, women with AF are generally more symptomatic, seek more care for symptoms and report lower quality of life (QoL).1 8 9 11 12 Despite this higher symptom load, available data suggest that women are less likely to undergo rhythm control, including AF ablation.2 10 13 14 Progression of AF has been associated with an increased risk of cardiovascular morbidity and mortality and reduced efficacy of pharmacological and interventional rhythm control strategies.15 Data on sex differences in AF progression are lacking, but probably differ since the prevalence of the most established associated risk factors and comorbidities for AF progression is not similar among sexes.16
The RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) study developed a new AF progression risk prediction model in patients with paroxysmal AF.17 18 The aims of this prespecified subanalysis of the RACE V trial were to assess (1) whether there are sex-specific differences in clinical presentation and QoL of patients with paroxysmal AF and (2) whether the incidence and determinants of AF progression differ between sexes using extensive phenotyping at baseline and continuous rhythm monitoring during follow-up.
Methods
The RACE V study has been previously described.17 19 In brief, the RACE V is an investigator-initiated, prospective, Dutch multicentre registry (ClinicalTrials.gov identifier NCT02726698) which included 658 patients from multiple centres in the Netherlands. This subanalysis includes 417 patients, all having a follow-up duration of ≥1 year.20 No patients were lost to follow-up in this first year or died before AF progression. Patients or the public were not involved in the design, or conduct, or reporting or dissemination plans of our research.
Trial population
A detailed overview of the inclusion and exclusion criteria has been previously described.19 Briefly, we included patients with a history of paroxysmal AF <10 years. Eligible patients had at least two documented episodes of paroxysmal AF or one documented episode combined with two or more symptomatic episodes suspected of being AF, were willing to undergo implantation of a Medtronic (Minneapolis, USA) Reveal LINQ implantable loop recorder, and did not have a history of persistent AF, had (intention to undergo) pulmonary vein isolation (PVI) or on current amiodarone treatment. Patients with Medtronic pacemakers were also eligible if atrial high rate episodes of >190 beats per minute lasting >6 min, qualified as AF episodes, were detected. For the current analysis, we included patients who had ≥1 year of continuous rhythm monitoring as of 1 May 2020. No patients were lost to follow-up or died in the first year.
Clinical assessment
At baseline, clinical history, symptomatology, current medication, physical examination and 12-lead ECG were assessed. Additionally, echocardiography, vascular assessment and cardiac CT were done and processed and analysed in a central core lab, as described previously.19 Cardiac CT was performed to assess coronary calcium scores (Agatston) and epicardial and pericardial fat. Vascular assessment of the carotid arteries included measurements of intima media thickness, pulse wave velocity and plaques.
Quality of life
At baseline, 1 year and 2.5 years of follow-up, the severity of AF-related symptoms was evaluated through self-reporting by each patient, using Part C of the University of Toronto Atrial Fibrillation Severity Scale (AFSS). The AFSS is a disease-specific tool designed to assess the severity of symptoms associated with AF. This seven-item questionnaire encompasses prevalent AF symptoms experienced at rest (such as palpitations, dyspnoea, fatigue, dizziness and chest pain) as well as during physical exertion (specifically dyspnoea and fatigue). Each symptom severity is assessed on a 6-point scale, ranging from 0 to 5 points. The total score, ranging from 0 to 35 points, reflects the overall severity of AF symptoms, with higher scores indicating greater symptom severity.
Furthermore, health-related QoL was evaluated at baseline, 1 year and 2.5 years of follow-up using the EQ-5D-5L questionnaire. This instrument incorporates a visual analogue scale that requires patients to rate their current health state on a scale from 0 (representing the worst imaginable health state) to 100 (representing the best imaginable health state). One of the items assessed is the level of anxiety.
Blood biomarkers
At baseline, peripheral blood samples were collected. Patients needed to be in sinus rhythm during blood sampling and oral anticoagulation temporarily interrupted. All blood samples were processed and stored at −80°C. With multiplex immunoassays, 92 cardiovascular biomarkers from the Olink Cardiovascular III panel were assessed by Olink Bioscience (Uppsala, Sweden) on EDTA plasma baseline samples (online supplemental table S1). Complexes of activated coagulation enzymes (FXIIa, FXIa, FIXa, FXa and thrombin) with their corresponding natural inhibitor (antithrombin, alpha1-antitrypsin or C1 esterase inhibitor) ELISAs were performed to assess the degree of coagulation activity on EDTA plasma and citrated plasma samples at baseline (online supplemental table S2).
Follow-up
All patients were treated according to the European Society of Cardiology AF guidelines.3 Follow-up visits were performed at 1 and 2.5 years. Patients could consent for 2.5 years of continuous rhythm monitoring until the end of battery of the Reveal LINQ or for 4 years in case patients had a pacemaker. In order to collect continuous data on arrhythmias, all patients received a home monitoring device (Medtronic Carelink). Both the Reveal LINQ and the pacemaker were set to atrial tachycardie (AT)/AF detection settings.
AF progression
As described previously, AF progression was defined as (1) the development of persistent or permanent AF during follow-up or (2) an increase of >3% AF burden over the first 6 months or total follow-up.18 The 3% cut-off has been published previously, and details concerning the 3% cut-off for AF burden can be found in the paper by Nguyen et al.19–21 The duration of monitoring for the current analysis lasted until 1 May 2020, until the last available rhythm monitoring for patients who died after >1 year of continuous rhythm monitoring or until the date of PVI in case of a successful PVI.
Statistical analysis
Baseline characteristics are presented as mean±SD for normally distributed data, and median and interquartile range (IQR) for non-normally distributed continuous data. Categorical data are presented as numbers with percentages. Fisher’s exact test was used for binary variables, and t-test or Wilcoxon rank-sum test was used for continuous variables. Variables with a p value smaller than 0.10 in the age-adjusted and sex-adjusted analyses were included in a bidirectional stepwise variable selection, leading to a final multivariable logistic regression model. Bidirectional stepping was done for model building and reduction, with a p value ≥0.05 as a criterion for removing a variable from the model. Imputation was implemented for missing values using the R package mice. For each logistic regression, ‘massive imputation’ was performed, which means that all variables in a model were at the same time also used for the imputation needed for the fit of that model. Interactions between variables were tested and no significant interactions were found, taking into account multiple testing using Bonferroni correction. P value <0.05 was considered statistically significant, except where Sidak or Bonferroni correction for multiple testing was applied to the significance level. The occurrence of AF progression between sexes was assessed by Kaplan-Meier curves and compared using a log-rank test. Analyses were conducted with R V.3.3.3.
Results
A total of 179 women and 238 men were included in the RACE V study (table 1). At baseline, women were significantly older (67 years vs 63 years, p<0.001), less often had coronary artery disease (n=11 (6%) vs n=36 (16%), p=0.003), had more obesity (n=57 (32%) vs n=50 (21%), p=0.013), had less epicardial and pericardial fat (median 144 (IQR 94–191) mL vs 199 (IQR 146–248) mL, p<0.001; and median 89 (IQR 61–121) mL vs 105 (IQR 83–133) mL, p<0.001, respectively) and had more impaired left atrial function. The median CHA2DS2-VASc score was higher in women (3 vs 2, p<0.001) and they experience more symptoms as measured by the European Heart Rhythm Association (EHRA) score.
Baseline characteristics, categorised by sex
The median follow-up was 2.2 (1.6–2.8) years. In terms of AF progression, a total of 51 out of 417 patients (5.5% per year) showed progression. Figure 1 shows that progression differed between women and men; 15 of 179 (8.4%) women and 36 of 238 (15.1%) men progressed (p=0.032). Progression to persistent or permanent AF occurred in 10 (5.6%) women vs 25 (10.5%) men; progression of self-terminating paroxysmal AF to >3% burden increase was seen in 5 (2.8%) women vs 11 (4.6%) men, respectively. Sex-related differences in the clinical characteristics of women and men with or without AF progression are shown in table 2.
Differences in the incidence of atrial fibrillation (AF) progression between women and men.
Differences in clinical characteristics between women and men with and without AF progression
Symptoms and QoL at baseline and during follow-up
The EHRA class was higher in women (p=0.002 for group comparison) (table 1). Figure 2 shows the differences in QoL as assessed by the AFSS. Women more often experienced palpitations throughout follow-up (baseline: 1.3±0.10 vs 0.8±0.07, p=0.002; 1-year follow-up 1.1±0.10 vs 0.7±0.07, p=0.005). They also experienced more shortness of breath during exercise at 1 year (1.4±0.11 vs 1.1±0.09, p=0.033). At that time, women experienced more often tiredness both at rest and during little exercise (p value for both comparison <0.001). No differences between the total AFSS score and the EQ-5D-5L questionnaire were observed (figure 3). Both women and men who suffered from anxiety as assessed by the EQ-5D-5L questionnaire had lower AFSS and EQ-5D-5L health scores as compared with those who did not. The AFSS score at baseline for women with anxiety was 10.8±1.0 vs 5.9±0.5 (p<0.001) and the health score was 69.8±2.3 with anxiety vs 78.0±1.1 without anxiety (p<0.001). For men with anxiety, the AFSS score at baseline was 9.9±0.8 vs 4.6±0.4 (p<0.001) and the health score 69.5±2.0 for those with anxiety and 81.2±0.8 for those without anxiety (p<0.001).
Sex differences in atrial fibrillation symptom severity (as assessed by the Atrial Fibrillation Severity Scale components); 0 signifies the absence of occurrence, while 5 indicates a significant level of distress or impact experienced. *P<0.05, **P<0.01, ***P<0.001.
Role of anxiety in symptom severity and quality of life in men and women. Anxiety was defined according to the EQ-5D-5L questionnaire. AFSS, Atrial Fibrillation Severity Scale.
Determinants of AF progression in women and men
The baseline levels of the 92 Olink biomarkers and coagulation markers are presented in online supplemental tables S1 and S2. Differences in Olink and coagulation biomarkers in women and men with or without AF progression are provided in online supplemental tables S3 and S4. Table 3 shows the results of the multivariable analysis assessing the parameters associated with AF progression in women and men. In women, decreased tissue factor pathway inhibitor (TFPI) (OR 2.22, 95% CI 1.24 to 3.99, p=0.008), higher N-terminal prohormone brain natriuretic peptide (NT-proBNP) (OR 2.10, 95% CI 1.15 to 3.83, p=0.016) and longer PR interval (OR 1.72, 95% CI 1.04 to 2.84, p=0.034) were associated with AF progression. In men, multivariable factor XIIa:C1 esterase inhibitor (median) (OR 3.06, 95% CI 1.32 to 7.08, p=0.009), higher NT-proBNP (OR 2.01, 95% CI 1.33 to 3.04, p<0.001) and higher proprotein convertase subtilisin/kexin type 9 (PCKS9) (OR 1.60, 95% CI 1.12 to 2.29, p=0.011) were associated with AF progression. Interaction analysis showed no significant differences in sex, clinical parameters and AF progression.
Multivariable logistic regression analysis assessing parameters associated with atrial fibrillation progression in women and men
Discussion
In this predefined analysis of the RACE V registry, we found important data on sex differences in patients with paroxysmal AF. First, the clinical profile is importantly different between women and men, and women more often had symptoms. In addition, the rate of AF progression was lower in women. The determinants of AF progression were also not similar between sexes, suggesting distinct underlying pathophysiological mechanisms playing a role in AF progression.
Differences in clinical, echocardiographic and blood biomarker characteristics between sexes
In line with published data, we describe the differences in clinical profile of women and men with PAF.12 Women included in the RACE V study were significantly older and less often had coronary artery disease, which was further supported by the observed lower calcium score on CT scan (as a derivate risk factor for coronary artery disease). In addition, the amount of epicardial and pericardial fat was lower. The pivotal role of risk factors and comorbidities in the AF pathophysiology, incident AF and AF progression is well known.18 Our most important finding is that, in patients with paroxysmal AF, AF progression is significantly lower in women as compared with men. Looking at differences between women with and without AF progression and men with and without AF progression, we observed another remarkable difference between sexes. In women, we did not find any clinical difference between those who progressed and those who did not, whereas men with AF progression more often had a history of coronary artery disease (as also illustrated by a higher calcium score), heart failure with reduced ejection fraction, more comorbidities, a wider waist circumference and slightly lower estimated glomerular filtration rate. One might argue that an underlying heart disease is of importance in the AF progression for men only; however, we must acknowledge that our data are limited by the small proportion of women who experienced AF progression. The observation that women with paroxysmal AF showed a lower progression rate was unexpected but is in line with more recent data showing that women do not necessarily have worse outcomes.8 22 23
We also explored whether there were differences in the underlying pathophysiological mechanisms for AF progression between women and men, assessing the role of 101 blood biomarkers including coagulation markers. For women and men, different blood biomarkers were in part found to be associated with AF progression, suggesting distinct underlying pathophysiological factors contributing to AF progression. In women, TFPI, prolonged PR interval and NT-proBNP were associated with AF progression, and in men NT-proBNP, PCKS9 and factor XIIa:C1 esterase inhibitor. Differences in blood biomarkers associated with AF progression between sexes have not been studied before. Both in women and men, hypercoagulability seemed to play a role, as suggested by lower levels of TFPI and increased activity of factor XIIa:C1 esterase inhibitor, respectively, suggesting a role of hypercoagulability in driving AF progression as previously shown in preclinical studies.24 In addition, both in women and men, NT-proBNP was an independent marker of risk of AF progression. Although it is well known that NT-proBNP is increased during AF, even without overt heart failure,16 the association with AF progression again stresses the intertwined relationship between AF and heart failure and calls for more improvement in diagnostic methods assessing heart failure during AF.25 26 A longer PR interval and/or an enlarged left atrium as signs of more severe atrial electroanatomical remodelling (atrial cardiomyopathy) promoting AF progression were observed in women but not in men and this is in line with previous studies showing that PR interval is associated with incident AF.27 The fact that it was only observed in women may relate to different associated comorbidities between sexes.1 2 4 In contrast, higher levels of PCSK9 were associated with AF progression in men. Higher levels of PCKS9 are suggested to be associated with cardiovascular events in patients with AF, possibly through atherosclerosis and inflammation,28 and are in agreement with the fact that men more often suffer from coronary artery disease as an associated comorbidity.
Symptoms and QoL
Although women included in our study reported more symptoms, the QoL as assessed by the AFSS and the EQ-5D-5L questionnaire was not different between women and men, which is in contrast to previous studies.1 11 This might be because only patients with paroxysmal AF were selected for the present study, whereas Kloosterman et al12 assessed the symptoms and quality of life in patients with PAF and persistent AF undergoing ablation and Lip et al investigated all patterns of AF.1 However, it may also relate to the fact that we included patients with paroxysmal AF and relatively low AF burden. It is likely that these questionnaires do not capture AF symptoms, but more likely symptoms related to the associated comorbidities; therefore, symptoms may not be related to the AF itself but to the associated comorbidities as well.29 Of interest is our observation that those patients who experienced anxiety had worse QoL in both sexes. Future research is warranted whether there is a relationship between AF and stress, initiated by modulation of the immune and autonomic nervous systems by stress.30
Strengths and limitations
Strengths include the well-phenotyped cohort and availability of continuous rhythm monitoring for the total follow-up duration. Limitations include the modest sample size (specifically women), the limited follow-up duration and the observational nature. Although the subanalysis was prespecified, the limitations of the current study are the same as those of other multicentre observational studies, such as potential bias in patient selection, referral and treatment. In patients with PAF and relatively low AF burden, questionnaires were used to assess AF symptoms and QoL. It is likely that these questionnaires did not only capture AF symptoms. Also, there may be bias in patient selection. For example, referral of patients with paroxysmal AF from the general practitioner to the hospital may be different (later) for women and men. Also, the willingness of patients to be included in the trial may vary among women and men at different ages. Furthermore, for women, an insight into the association of hormones and biomarker expression in women in residual confounding may have impacted the multivariable analyses. Longer follow-up would furthermore lead to more robust analyses, considering the relatively short follow-up. Also, we did not take death into account as a competing event. Furthermore, whether PVI may have led to slower rate of progression is unknown.
Conclusions
The clinical profile of women and men with paroxysmal AF is different. Despite older age, the prevalence of AF progression was lower in women than in men. Determinants associated with AF progression varied between sexes, suggesting different pathophysiological mechanisms in women and men. Interestingly, in both women and men, hypercoagulation seems to play a role in AF progression.
Data availability statement
Data are available upon reasonable request. The data underlying this article are available on request from the principal investigator.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Medische Ethische Toetsings Commissie van de Universiteit Medisch Centrum Groningen (METc UMCG) (METc number: METc 2016/16) and the institutional review board of all participating centres. The study was performed in compliance with the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
BAM and NKE are joint first authors.
Contributors BAM, NKE, ICVG, HJC and MR designed the study. BAM, NKE, ICVG and MR drafted the manuscript. BG and BAM performed all statistical analyses. All authors provided substantial contributions to data interpretation and critical revisions and approved the final manuscript. BAM, NKE, ICVG and MR are responsible for the overall content as guarantor and thereby accept full responsibility for the finished work and the conduct of the study, including access to the data.
Funding We acknowledge support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (CVON 2014-9): Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF (RACE V); and unrestricted grant support from Medtronic Trading NL BV.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.